There is a fundamental gap in our understanding of how animal virus interactions with cell surface receptors facilitate a productive infection. Bindin of viruses, such as herpesviruses, to the cell surface can occur at 40C in an energy independent manner. In contrast, entry into cells and subsequent transfer of capsids to the vicinity of the nucleus are an active, energy dependent phenomenon, and thus must require host-cell signaling pathways. Our central hypothesis is that KSHV has evolved to utilize its interactions with receptors to manipulate the host's pre-existing signal cascades to mediate entry and infection of target cells. Our ongoing studies support this hypothesis. We have shown that during infection of endothelial (HMVEC-d) cells, the initial attachment of KSHV occurs via heparan sulfate (HS) followed by a temporal interaction with integrins (?3?1,??V??3, and ?V??5) and xCT molecules. KSHV binding resulted in the activation of FAK, Src, PI3-K, Rho-GTPases, Dia-2, Ezrin, PKC-?, ERK1/2 and NF-?B signal molecules. These molecules play roles in KSHV entry (FAK, Src, PI3-K, Rho-GTPases), acetylation of microtubules (MT) (RhoA-GTPase) that facilitates the transport of KSHV capsid toward the nucleus via dynein motors, and viral gene expression (ERK1/2 and NF-?B). Although lipid raft (LR) disruption resulted in increased Src activation and virus entry, we observed the inhibition of viral gene expression, PI3K, RhoA, Dia-2 and NF?B activation, MT acetylation and nuclear delivery of viral DNA which suggested that LRs play roles in entry in cells and modulates selected signal molecules. We have also demonstrated that c-Cbl play a role in KSHV macropinocytosis. To further test our hypothesis, we have formulated three major interlinked, focused specific aims which will decipher the mechanisms by which c-Cbl facilitate KSHV entry, the role of major adaptor molecules in KSHV infection and decipher how c-Cbl dictates the fate of macropinosomes containing KSHV. These studies are significant since such comprehensive understanding of early events of KSHV infection will provide novel targets to block the initiation of target cell infection by KSHV and te associated diseases.